The major components of amyloid plaque in Alzheimer's disease (AD) brain are 39-42 amino acid peptides called Abeta that are derived from proteolytic processing of the amyloid precursor protein (APP). The majority of early onset familial AD cases are caused by autosomal dominant mutations in the genes encoding presenilin (PS) proteins 1 and 2 and APP. Mutations in PS1 and PS2 alter APP processing and result in an increase in the production of the highly fibrillogenic 42 amino acid Abeta 42 peptide. Studies have shown that dominant negative mutant presenilins enhance the delivery of full-length APP to the cell surface, and that more APP accumulates in early compartments of the secretory pathway. This proposal outlines studies to characterize the kinetics of APP transport early in the secretory pathway between the endoplasmic reticulum (ER) and Golgi complex to identify where PS1 exerts its influence on the biogenesis and trafficking of newly synthesized APP. Furthermore, we plan to identify which domain(s) of APP are important for the influence of PS1 on APP biogenesis and trafficking to the cell surface by generating CD8/APP chimeras. Finally, we will investigate the general role of PS in trafficking of other type I membrane proteins by examining the maturation of well-characterized control proteins using wild-type PSi, mutant PS1, and PS1/PS2 knockout cell lines.